VXM01 is a first-in-kind orally applied tumor vaccine based on live attenuated Salmonella typhi carrying an expression plasmid encoding VEGFR2, an antigen expressed on tumor vasculature and a stable and accessible target for anti-angiogenic intervention. A recent randomized, placebo-controlled, phase I dose-escalation trial in advanced pancreatic cancer patients demonstrated safety, immunogenicity and transient, T-cell response-related anti-angiogenic activity of four priming vaccinations applied within one week. We here evaluated whether monthly boost vaccinations are safe and can sustain increased frequencies of vaccine-specific T cells. Patients with advanced pancreatic cancer were randomly assigned at a ratio of 2:1 to priming with VXM01 followed by up to six monthly boost vaccinations, or placebo treatment. Vaccinations were applied orally at two alternative doses of either 106 colony-forming units (CFU) or 107 CFU, and concomitant treatment with standard-of-care gemcitabine during the priming phase, and any treatment thereafter, was allowed in the study. Immunomonitoring involved interferon-gamma (IFNγ) ELIspot analysis with long overlapping peptides spanning the entire VEGFR2 sequence. A total of 26 patients were treated. Treatment-related adverse events preferentially associated with VXM01 were decreases in lymphocyte numbers in the blood, increased frequencies of neutrophils and diarrhea. Eight out of 16 patients who received at least one boosting vaccination responded with pronounced, i.e. at least 3-fold, increase in VEGFR2-specific T cell response over baseline levels. In the VXM01 vaccination group, VEGFR2-specific T cells peaked preferentially during the boosting phase with an average 4-fold increase over baseline levels. In conclusion, prime/boost vaccination with VXM01 was safe and immunogenic and increased vaccine specific T cell responses compared with placebo treatment.

中文翻译：

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一项1期试验扩展，用于评估晚期胰腺癌患者初次免疫接种VXM01（针对VEGFR2的口服T细胞疫苗）的免疫效力和安全性。

VXM01是第一种基于口服减毒活伤寒沙门氏菌的口服肿瘤疫苗，携带的编码质粒编码VEGFR2，在肿瘤脉管系统上表达的抗原以及稳定且易于接近的抗血管生成干预靶标。最近的一项针对晚期胰腺癌患者的随机，安慰剂对照，I期剂量递增试验显示，在一周内进行了四种初免疫苗接种，具有安全性，免疫原性以及与T细胞反应相关的短暂，抗血管生成活性。我们在这里评估了每月加强免疫是否安全并且能否维持疫苗特异性T细胞频率的增加。晚期胰腺癌患者以2：1的比例随机分配给初次接受VXM01的患者，随后每月进行六次加强免疫或安慰剂治疗。口服疫苗接种有两种替代剂量，即106个菌落形成单位（CFU）或107 CFU，并在初免阶段伴随用护理标准的吉西他滨治疗，此后的任何治疗均被允许。免疫监测涉及干扰素-γ（IFNγ）ELIspot分析，跨整个VEGFR2序列的长重叠肽段。总共治疗了26例患者。优先与VXM01相关的与治疗有关的不良事件是血液中淋巴细胞数量减少，中性粒细胞发生频率增加和腹泻。在接受至少一次加强疫苗接种的16名患者中，有八名患者的VEGFR2特异性T细胞应答明显高于基线水平，即增加了至少三倍。在VXM01疫苗接种组中，VEGFR2特异性T细胞在加强阶段优先达到峰值，比基线水平平均增加4倍。总之，与安慰剂治疗相比，用VXM01初免/加强免疫接种是安全，具有免疫原性和增加的疫苗特异性T细胞反应。